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. 2014 Apr;99(4):743-50.
doi: 10.3324/haematol.2013.095463. Epub 2013 Nov 8.

Oral Melphalan and Dexamethasone Grants Extended Survival With Minimal Toxicity in AL Amyloidosis: Long-Term Results of a Risk-Adapted Approach

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Oral Melphalan and Dexamethasone Grants Extended Survival With Minimal Toxicity in AL Amyloidosis: Long-Term Results of a Risk-Adapted Approach

Giovanni Palladini et al. Haematologica. .
Free PMC article

Abstract

The combination of oral melphalan and dexamethasone is considered standard therapy for patients with light-chain amyloidosis ineligible for autologous stem cell transplantation. However, previous trials reported different rates of response and survival, mainly because of the different proportions of high-risk patients. In the present study, including a total of 259 subjects, we treated 119 patients with full-dose melphalan and dexamethasone (dexamethasone 40 mg days 1-4), and 140 patients with advanced cardiac disease with an attenuated dexamethasone schedule (20 mg). Hematologic response rates were 76% in the full-dose group and 51% in the patients receiving the attenuated schedule; the corresponding complete response rates were 31% and 12%, respectively. The median survival was 7.4 years in the full-dose group and 20 months in the attenuated-dose group. Use of high-dose dexamethasone, amino-terminal pro-natriuretic peptide type-B >1800 ng/L, a difference between involved and uninvolved free light chains of >180 mg/L, troponin I >0.07 ng/mL, and response to therapy were independent prognostic determinants. In relapsed/refractory subjects bortezomib combinations granted high hematologic response rates (79% and 63%, respectively), proving the most effective rescue treatment after melphalan and dexamethasone. In summary, melphalan plus dexamethasone was highly effective with minimal toxicity, confirming its central role in the treatment of AL amyloidosis. Future randomized trials will clarify whether bortezomib is best used in frontline combination with melphalan and dexamethasone or as rescue treatment.

Figures

Figure 1.
Figure 1.
Survival and time to second-line therapy or death according to treatment intensity. (A) Overall survival (median 88 vs. 20 months, P<0.001). (B) Time to second-line therapy or death (median 30 vs. 13 months, P<0.001).
Figure 2.
Figure 2.
Survival according to the revised staging system. The revised staging system is based on NT-proBNP (cutoff 1800 ng/L), cTnI (cutoff 0.07 ng/mL), and dFLC (cutoff 180 mg/L). Stage I, II, III, and IV patients have none, one, two or three markers above the cutoffs, respectively. Stage I, median survival not reached. Stage II, median survival 52 months (P=0.003 compared to stage I). Stage III, median survival 19 months (P=0.003 compared to stage II). Stage IV, median survival 7 months (P=0.030 compared to stage III).
Figure 3.
Figure 3.
Survival according to response to treatment (3-month landmark analysis). (A) Overall survival according to hematologic response. Complete response (CR), median survival not reached. Very good partial response (VGPR), median 78 months (P=0.001 compared to CR). Partial response (PR), median 39 months (P=0.029 compared to VGPR). No response (NR), median 17 months (P=0.009 compared to PR). (B) Time to second-line therapy or death according to hematologic response. CR, median not reached. VGPR, median 25 months (P<0.001 compared to CR). PR, median 17 months (P=0.049 compared to VGPR). NR, median 7 months (P=0.006 compared to PR).
Figure 4.
Figure 4.
Survival according to hematologic response in the different risk stages. (A) Stage I. Median 60 months vs. not reached (P=0.003). (B) Stage II. Median 31 months vs. not reached (P=0.001). (C) Stage III. Median 11 vs. 59 months (P=0.001). (D) Stage IV. Median 7 vs. not reached (P=0.001).

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